US5948800A - Preventive or therapeutic drug for Alzheimer's disease - Google Patents
Preventive or therapeutic drug for Alzheimer's disease Download PDFInfo
- Publication number
- US5948800A US5948800A US08/905,530 US90553097A US5948800A US 5948800 A US5948800 A US 5948800A US 90553097 A US90553097 A US 90553097A US 5948800 A US5948800 A US 5948800A
- Authority
- US
- United States
- Prior art keywords
- administered
- phenyl
- benzisoselenazol
- composition
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention relates to a preventive or therapeutic drug for Alzheimer's disease containing as the active ingredient 2-phenyl-1,2-benzisoselenazol-3(2H )-one, whose effect is based on the action of reducing neuron toxicity induced by ⁇ -amyloid protein.
- acetylcholinesterase inhibitors such as physostigmine or tetrahydroaminoacridine (THA) are used as preventive or therapeutic drugs for Alzheimer's disease.
- TAA tetrahydroaminoacridine
- Pathological traits of Alzheimer's disease include senile plaques and accumulation of PHFs (paired helical filaments) in the brain.
- a ⁇ The ⁇ -amyloid protein (hereinafter referred to as A ⁇ ), which is the main component of senile plaques, is an insoluble peptide constituted by approximately 40 amino acid residues. It has been elucidated that A ⁇ itself damages neurons biochemically, and particularly that coagulated A ⁇ --not solubilized A ⁇ --is responsible for this effect.
- the present inventors conducted extensive studies toward finding low molecular compounds that are capable of passing through the brain blood flow barrier (BBB) and that have an effect of reducing neuron toxicity of A ⁇ , and found that 2-phenyl-1,2-benzisoselenazol-3(2H)-one (herein after referred to as compound A) has an excellent action, leading to completion of the present invention.
- BBB brain blood flow barrier
- compound A 2-phenyl-1,2-benzisoselenazol-3(2H)-one
- Compound A which is used in the present invention has an effect of inhibiting the death of neurons, which death is caused in the presence of A ⁇ .
- use of compound A as a preventive or therapeutic drug for Alzheimer's disease is expected.
- a ⁇ was identified as a main constituent of senile plaques, one of the pathological traits of Alzheimer's disease. It is composed of 39-43 amino acid residues. It is also known that A ⁇ aggregates and exhibits neurotoxicity to induce cellular death. It has recently been found that death of PC12 cells in the presence of A ⁇ , attributed to neurotoxic A ⁇ , is suppressed when compound A (ebselen) is added. Therefore, compound A is expected to be an excellent preventive or therapeutic drug for Alzheimer's disease.
- Compound A used in the present invention may be synthesized through a process disclosed in Japanese Patent Publication (kokoku) No. 2-38591 (Japanese Patent Application Laid-Open (kokai) No. 57-67568).
- Compound A may be produced by reaction of 2-methylseleno-2-phenyl-benzamide with phosphorous pentachloride and subsequent hydrolysis, as described in U.S. Pat. No. 4,757,063 (Parnham) and in R. Weber et al., Bulletin de la Soc. Chim de France, 1986 (7/8), pgs. 1124-1126. All of the foregoing references are incorporated herein by reference.
- Compound A can be transformed into various forms such as tablets, capsules, powders, granules, syrups, and injections using known formulation techniques together with additives including vehicles, binders, disintegrants, and solubilizers.
- Compound A exerts its primary expected effect in any manner of administration, e.g., ordinary oral administration or peroral administration such as injection.
- the dose of compound A is between 100 and 2,000 mg/day for an adult, and preferably between 200 and 1,000 mg/day, which may be suitably increased or decreased depending on the clinical condition of the patient.
- Toxicity of compound A has been studied by obtaining LD 50 values in mice and rats.
- the LD 50 values obtained on mice were ⁇ 6,810 mg/kg in the case of oral administration, and 740 mg/kg in the case of intraperitoneal administration.
- the LD 50 values obtained on rats were ⁇ 6,810 mg/kg in the case of oral administration, and 580 mg/kg in the case of intraperitoneal administration.
- these LD 50 values prove that compound A is a very safe compound.
- PC12 cells (derived from rats, chromaffin tumor) were cultured and subcultured in a 100 mm dish (made of Corning) coated with polylysine and containing a DMEM medium supplemented with 10% FCS and 5% horse serum (product of Sigma). Briefly, PC12 cells (1 ⁇ 10 6 cells/dish) were seeded in a 100 mm dish coated with polylysine. In order to induce differentiation of the PC12 cells, the cells were grown for 7 days in a DMEM medium containing 5% FCS, 50 ng/ml NGF, and 1% horse serum. The PC12 cells were then peeled off through pipetting and suspended in a suitable medium to prepare a cell suspension.
- the cell suspension was seeded into each well of a polylysine-coated 96-well dish (1 ⁇ 10 4 cells/well). Subsequently, A ⁇ (Bachem Feinchmikalien AG) was added so that a final concentration of 10 ⁇ M was achieved. Compound A was also added so that a final concentration of 0.1, 1.0, or 2.5 ⁇ M was achieved. As controls, compound B (compound A substituted by sulfur; having no glutathione peroxidase-like activities; 2-phenyl-1,2-benzothiazol-3(2H)-one; provided by Nattermann) was added at the same concentrations in a similar manner. The cells were cultured for 48 hours from the addition of compound A or compound B.
- MTT reagent 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide
- incubation was performed for 4 hours, and the cells were lysed.
- the subsequent procedure was performed using a so-called MTT method, which employs colorimetry based on a reduction reaction of the reagent, to thereby obtain the viability of the cells in the suspension (Behl, C. et al., Cell, 77: 817-827, 1994).
- PC12 cells (derived from rats, chromaffin tumor) were cultured and subcultured in a 100 mm dish (made of Corning) coated with polylysine and containing a DMEM medium supplemented with 10% FCS and 5% horse serum (product of Sigma). Briefly, PC12 cells (1 ⁇ 10 6 cells/dish) were seeded in a 100 mm dish coated with polylysine. In order to induce differentiation of the PC12 cells, the cells were grown for 7 days in a DMEM medium containing 5% FCS, 50 ng/ml NGF, and 1% horse serum. The PC12 cells were then peeled off through pipetting and suspended in a suitable medium to prepare a cell suspension. The cell suspension was seeded into each well of a 60 mm, polylysine-coated 96-well dish (1 ⁇ 10 4 cells/well). After adhesion of the cells was confirmed, the following procedure was performed.
- PC12 cells were placed in a DMEM medium. To the cells were added 10 ⁇ M of SNAP and 2.5 ⁇ M of compound A. For control groups, only SNAP was added. Each sample was incubated for 3 hours. Thereafter, a solution of DCFH-DA (Molecular Probes, Inc.) in DMSO (1 mg/413 ⁇ l) which had been prepared in advance was added to each PC12-containing sample so that a final concentration of 5 ⁇ M was obtained, and the samples were then incubated for 30 minutes. The cells were removed using trypsin-EDTA, and recovered via centrifugation (1,000 rpm ⁇ 5 min.). The recovered cells were suspended in 50 ⁇ l of PBS(-) while being cooled with ice.
- DCFH-DA Molecular Probes, Inc.
- the amount of intracellular hydrogen peroxide was determined using a flow cytometer;
- the cell suspension was subjected to FACS (fluorescence-activated cell sorting), and the amount of the fluorescent substance, 2',7'-dichlorofluorescin (DCFH), which had been oxidized by peroxides was measured.
- FACS fluorescence-activated cell sorting
- DCFH 2',7'-dichlorofluorescin
- apotosis may be related to the death of neurons in Alzheimer's disease. Also, there has been reported that death of neurons is triggered by A ⁇ , and the neurotoxicity is caused by the generation of hydrogen peroxide (Proc. Natl. Acad. Sci. USA., 90: 7951-7955, 1993).
- compound A significantly suppresses generation of hydrogen peroxide induced by A ⁇ . Therefore, it has been demonstrated that compound A is expected to provide excellent preventive or therapeutic effects on Alzheimer's disease.
- compound A which is used in the present invention is specifically useful as a preventive or therapeutic drug for senile dementia, in particular, Alzheimer's disease.
- Polylysine is a Lysine-Polypeptide with a variable chain length
- DMEM Delbecco's modified Eagle's medium
- DCFH is 2',7'-dichlorofluorescin
- FCS means fetal calf serum
- DMSO dimethyl sulphoxide
- Trypsin EDTA is a complexing agent on the basis of ethylendiamine tetraacetic acid and
- NO is nitrogen oxide
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JPH8-225512 | 1996-08-27 | ||
JP22551296 | 1996-08-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
US5948800A true US5948800A (en) | 1999-09-07 |
Family
ID=16830487
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/905,530 Expired - Lifetime US5948800A (en) | 1996-08-27 | 1997-08-04 | Preventive or therapeutic drug for Alzheimer's disease |
Country Status (29)
Country | Link |
---|---|
US (1) | US5948800A (hu) |
EP (1) | EP0826370B1 (hu) |
KR (1) | KR20000035859A (hu) |
CN (1) | CN1112922C (hu) |
AT (1) | ATE219361T1 (hu) |
AU (2) | AU3866997A (hu) |
BR (1) | BR9711259A (hu) |
CA (1) | CA2213794C (hu) |
CZ (1) | CZ295364B6 (hu) |
DE (2) | DE59707550D1 (hu) |
DK (1) | DK0826370T3 (hu) |
EE (1) | EE03953B1 (hu) |
ES (1) | ES2177849T3 (hu) |
FI (1) | FI119622B (hu) |
HK (1) | HK1020317A1 (hu) |
HU (1) | HU225264B1 (hu) |
IL (1) | IL127113A (hu) |
LT (1) | LT4602B (hu) |
LV (1) | LV12251B (hu) |
NO (1) | NO312812B1 (hu) |
NZ (1) | NZ332292A (hu) |
PL (1) | PL188481B1 (hu) |
PT (1) | PT826370E (hu) |
SI (1) | SI9720060B (hu) |
TR (1) | TR199700858A2 (hu) |
TW (1) | TW501925B (hu) |
UA (1) | UA59367C2 (hu) |
WO (2) | WO1998008511A1 (hu) |
ZA (1) | ZA977644B (hu) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6335036B1 (en) * | 1993-10-27 | 2002-01-01 | Daiichi Pharmaceutical Co., Ltd. | Granular pharmaceutical preparation of ebselen |
EP1174423A1 (en) * | 1999-03-31 | 2002-01-23 | Daiichi Pharmaceutical Co., Ltd. | Substrates for thioredoxin reductase |
US8901158B2 (en) | 2011-02-09 | 2014-12-02 | Isis Innovation Ltd. | Treatment of bipolar disorder |
EP2950102A1 (en) | 2014-05-30 | 2015-12-02 | Biocross, S.L. | Method for the diagnosis of alzheimer s disease and mild cognitive impairment |
EP3067699A1 (en) | 2015-03-11 | 2016-09-14 | Neuron Bio, S.A. | Method for diagnosing alzheimer's disease |
US10058542B1 (en) | 2014-09-12 | 2018-08-28 | Thioredoxin Systems Ab | Composition comprising selenazol or thiazolone derivatives and silver and method of treatment therewith |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2000016935A (ja) * | 1998-07-01 | 2000-01-18 | Dai Ichi Seiyaku Co Ltd | シクロオキシゲナーゼ阻害剤 |
WO2003010154A1 (en) * | 2001-07-26 | 2003-02-06 | Samsung Electronics Co. Ltd. | Seleno compounds containing nitrone moiety, their preparation and their therapeutic uses |
WO2003010153A1 (en) * | 2001-07-26 | 2003-02-06 | Samsung Electronics Co. Ltd. | N-alkyl-n-phenylhydroxylamine compounds containing metal chelating groups, their preparation and their therapeutic uses |
WO2003010143A1 (en) | 2001-07-26 | 2003-02-06 | Samsung Electronics Co., Ltd. | Dialkylhydroxybenzoic acid derivatives containing metal chelating groups and their therapeutic uses |
CN103965188A (zh) * | 2013-01-29 | 2014-08-06 | 中山大学 | 含硒多奈哌齐类似物 |
PL237739B1 (pl) | 2018-06-06 | 2021-05-17 | Univ Gdanski | Genisteina do zastosowania do leczenia choroby Alzheimera |
CN113116888B (zh) * | 2021-04-19 | 2022-08-26 | 上海兴糖生物技术有限公司 | 依布硒啉的用途 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4757063A (en) * | 1986-05-20 | 1988-07-12 | A. Nattermann & Cie. Gmbh | Process for the treatment of diseases caused by oxidative stress |
WO1992002221A1 (en) * | 1990-08-06 | 1992-02-20 | Rhone-Poulenc Rorer Gmbh | Use of 2-phenyl-1,2-benzisoselenazol-3(2h)-one |
US5246951A (en) * | 1990-11-23 | 1993-09-21 | Adir Et Compagnie | New benzoselenazolinone compounds |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3638124C2 (de) * | 1986-11-08 | 1996-09-05 | Nattermann A & Cie | Neue pharmazeutische Verwendung von Ebselen |
JPH01131113A (ja) * | 1987-08-27 | 1989-05-24 | Dai Ichi Seiyaku Co Ltd | 脳障害治療剤 |
JPH0238591A (ja) | 1988-07-27 | 1990-02-07 | Fujikura Ltd | 高純度銅の製造方法 |
US5385726A (en) * | 1990-08-06 | 1995-01-31 | Rhone-Poulenc Rorer Gmbh | Use of 2-phenyl-1,2-benzisoselenazol-3-(2H)-one |
JPH07233056A (ja) * | 1993-09-03 | 1995-09-05 | Dai Ichi Seiyaku Co Ltd | リポキシゲナーゼ阻害剤 |
-
1997
- 1997-03-17 DK DK97104503T patent/DK0826370T3/da active
- 1997-03-17 PT PT97104503T patent/PT826370E/pt unknown
- 1997-03-17 ES ES97104503T patent/ES2177849T3/es not_active Expired - Lifetime
- 1997-03-17 DE DE59707550T patent/DE59707550D1/de not_active Expired - Fee Related
- 1997-03-17 EP EP97104503A patent/EP0826370B1/de not_active Expired - Lifetime
- 1997-03-17 AT AT97104503T patent/ATE219361T1/de not_active IP Right Cessation
- 1997-04-07 SI SI9720060A patent/SI9720060B/sl not_active IP Right Cessation
- 1997-04-07 NZ NZ332292A patent/NZ332292A/en unknown
- 1997-04-07 HU HU9903213A patent/HU225264B1/hu not_active IP Right Cessation
- 1997-04-07 IL IL12711397A patent/IL127113A/xx not_active IP Right Cessation
- 1997-04-07 CN CN97195890A patent/CN1112922C/zh not_active Expired - Fee Related
- 1997-04-07 CZ CZ1999317A patent/CZ295364B6/cs not_active IP Right Cessation
- 1997-04-07 EE EEP199900007A patent/EE03953B1/xx not_active IP Right Cessation
- 1997-04-07 BR BR9711259A patent/BR9711259A/pt not_active Application Discontinuation
- 1997-04-07 WO PCT/DE1997/000701 patent/WO1998008511A1/de active IP Right Grant
- 1997-07-04 UA UA99010526A patent/UA59367C2/uk unknown
- 1997-08-04 US US08/905,530 patent/US5948800A/en not_active Expired - Lifetime
- 1997-08-04 DE DE19733690A patent/DE19733690A1/de not_active Withdrawn
- 1997-08-20 AU AU38669/97A patent/AU3866997A/en not_active Abandoned
- 1997-08-20 WO PCT/JP1997/002883 patent/WO1998008831A1/ja not_active Application Discontinuation
- 1997-08-20 KR KR1019997001554A patent/KR20000035859A/ko not_active Application Discontinuation
- 1997-08-21 TW TW086112018A patent/TW501925B/zh not_active IP Right Cessation
- 1997-08-25 CA CA002213794A patent/CA2213794C/en not_active Expired - Fee Related
- 1997-08-26 NO NO19973912A patent/NO312812B1/no not_active IP Right Cessation
- 1997-08-26 AU AU35298/97A patent/AU725534B2/en not_active Ceased
- 1997-08-26 ZA ZA977644A patent/ZA977644B/xx unknown
- 1997-08-26 PL PL97321796A patent/PL188481B1/pl not_active IP Right Cessation
- 1997-08-27 TR TR97/00858A patent/TR199700858A2/xx unknown
-
1998
- 1998-10-22 LV LVP-98-231A patent/LV12251B/lv unknown
- 1998-12-11 FI FI982689A patent/FI119622B/fi not_active IP Right Cessation
-
1999
- 1999-02-23 LT LT99-016A patent/LT4602B/lt not_active IP Right Cessation
- 1999-11-29 HK HK99105534A patent/HK1020317A1/xx not_active IP Right Cessation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4757063A (en) * | 1986-05-20 | 1988-07-12 | A. Nattermann & Cie. Gmbh | Process for the treatment of diseases caused by oxidative stress |
WO1992002221A1 (en) * | 1990-08-06 | 1992-02-20 | Rhone-Poulenc Rorer Gmbh | Use of 2-phenyl-1,2-benzisoselenazol-3(2h)-one |
US5246951A (en) * | 1990-11-23 | 1993-09-21 | Adir Et Compagnie | New benzoselenazolinone compounds |
Non-Patent Citations (6)
Title |
---|
"Ebselen (PZ-51) Protects the Caudate Putamen Against Hypoxia/Ischemia Induced Neuronal Damage," Knollema et al., Neuroscience Research Communications, vol. 19, No. 1, Jul.-Aug. 1996, pp. 47-56. |
"The neuroprotective efficacy of ebselen (a glutathione peroxidase mimic) on brain damage induced by transient focal cerebral ischaemia in the rat," Dawson et al., Neuroscience Letters, 185 (1995) pp. 65-69. |
"The Role of Free Radicals in Toxicity and Disease," Sidney J. Stohs, Journal of Basic and Clinical Physiology and Pharmacology, vol. 6, No. 3-4, 1995, pp. 205-228. |
Ebselen (PZ 51) Protects the Caudate Putamen Against Hypoxia/Ischemia Induced Neuronal Damage, Knollema et al., Neuroscience Research Communications , vol. 19, No. 1, Jul. Aug. 1996, pp. 47 56. * |
The neuroprotective efficacy of ebselen (a glutathione peroxidase mimic) on brain damage induced by transient focal cerebral ischaemia in the rat, Dawson et al., Neuroscience Letters , 185 (1995) pp. 65 69. * |
The Role of Free Radicals in Toxicity and Disease, Sidney J. Stohs, Journal of Basic and Clinical Physiology and Pharmacology , vol. 6, No. 3 4, 1995, pp. 205 228. * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6335036B1 (en) * | 1993-10-27 | 2002-01-01 | Daiichi Pharmaceutical Co., Ltd. | Granular pharmaceutical preparation of ebselen |
EP1174423A1 (en) * | 1999-03-31 | 2002-01-23 | Daiichi Pharmaceutical Co., Ltd. | Substrates for thioredoxin reductase |
EP1174423A4 (en) * | 1999-03-31 | 2008-03-19 | Arne Holmgren | SUBSTRATES FOR THIOREDOXINE REDUCTASE |
US8901158B2 (en) | 2011-02-09 | 2014-12-02 | Isis Innovation Ltd. | Treatment of bipolar disorder |
EP2950102A1 (en) | 2014-05-30 | 2015-12-02 | Biocross, S.L. | Method for the diagnosis of alzheimer s disease and mild cognitive impairment |
US10058542B1 (en) | 2014-09-12 | 2018-08-28 | Thioredoxin Systems Ab | Composition comprising selenazol or thiazolone derivatives and silver and method of treatment therewith |
US11013730B1 (en) | 2014-09-12 | 2021-05-25 | Thioredoxin Systems Ab | Composition comprising selenazol or thiazalone derivatives and silver and method of treatment therewith |
EP3067699A1 (en) | 2015-03-11 | 2016-09-14 | Neuron Bio, S.A. | Method for diagnosing alzheimer's disease |
WO2016142450A1 (en) | 2015-03-11 | 2016-09-15 | Neuron Bio, S.A. | Method for diagnosing alzheimer's disease |
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